The introduction of 1-34rhPTH (TPTD) for treatment of individuals with osteoporosis at high risk of fracture changed the paradigm and gave clinicians an agent that has the capacity to correct the underlying architectural defect that is the hallmark of osteoporosis. Our group has a long-standing interest in the effects of TPTD on bone and have an ongoing study designed to look mechanistically at TPTD effects on bone, into which we have recruited 150 women with osteoporosis who were either treatment na[unreadable]ve or who had been previously treated with alendronate. These individuals are being followed for 2 yrs (4 three TPTD month cycles or 2 yrs daily treatment). This application is a logical extension of that ongoing study and takes advantage of this unique population of TPTD-treated patients to compare the effects of teriparatide given cyclically (8 three month cycles) over 4 years with teriparatide given daily for 2 years on BMD of the spine and hip by DXA and QCT and BMD and microstructure of the radius and tibia assessed by high resolution pQCT. The specific aims are to determine in treatment na[unreadable]ve and alendronate-treated subjects: 1. If TPTD given cyclically (3months on, 3 months off) over a 4 year period produces a clinically meaningful greater increase in BMD by DXA than 2 years of daily TPTD. 2. If QCT (hip, spine, radius and tibia), and FEA modeling of CT data, show enhanced effects of TPTD treatment or simply mirror DXA data. 3. If the tachyphylaxis seen with daily TPTD is caused by depletion of osteoblast precursors, and if it can be obviated by cyclic administration of TPTD. There is no other cohort, and nor will there be, any similar cohort in which these important and clinically relevant aims can be addressed. We believe that our population of subjects treated with TPTD allows us a unique opportunity to determine these clinically important long-term outcomes, since fracture studies with these TPTD regimens are unlikely to be undertaken. The issue of tachyphylaxis to ongoing TPTD administration, will be able to be assessed using the novel technique of an evaluation of the size of the circulating osteoblast pool in cyclic versus daily therapy. PUBLIC HEALTH RELEVANCE: In this clinical study we will determine the long-term effects of Teriparatide (Forteo or TPTD) on bone structure and strength, in a population of subjects already recruited into a 2 year clinical trial. This study will extend this unique trial by comparing the effects of 2 years of daily TPTD followed by alendronate (Fosamax) with a novel cyclic regimen in which TPTD is given for 3 month intervals followed by 3 month rest periods. The study will also compare the outcomes in women already on alendronate at the start of the protocol and continued on alendronate while being treated cyclically or continuously with TPTD. We will examine whether cyclic treatment can produce repeated stimuli to bone formation over 8 cycles and thus a greater increment in bone strength than 2 years of daily treatment where we know that the effects of TPTD generally decline. We will also test one theory for why this decline occurs, namely that the supply of the bone forming cells (osteoblasts) becomes depleted during the course of the daily regimen. We believe that the periods where no TPTD is given in the cyclic regimen will allow for ongoing recovery of the supply of osteoblasts and will ultimately results in greater gains in bone mass and strength.